Diabetes refers to a disease process derived from multiple causative factors. Generally speaking, there are two types of diabetes: type I and type II. Type I diabetes, also known as insulin-dependent diabetes mellitus (IDDM), is characterized by loss of pancreatic β-cells which are damaged in the process of autoimmunity. Type II diabetes, also known as non insulin dependent diabetic mellitus (NIDDM), which is more common and a long-term and progressive metabolic disease, is characterized by hyperglycemia, hyperlipidemia and insulin resistance. The typical symptoms of type II diabetes comprise polyuria, polydipsia and bulimia.
Incretin plays an important role in regulating blood sugar balance in normal and pathological states. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are two incretins released from intestine after food intake and have influence on insulin secretion. GLP-1 reduces hyperglycemia by promoting insulin secretion and reducing glucagon secretion in a glucose-dependent way. Meanwhile, GLP-1 can slow gastric emptying, suppress appetites, increase satiety and promote weight loss. In animal studies, GLP-1 is of nutritional function on β-cells, which increases the likelihood of improving disease's symptoms by increasing the density and function of β-cells. Recently, researches indicated that GLP-1 is beneficial to cardiovascular system. The finding is very important because cardiovascular complication is one of the leading causes of death in diabetic patients. In short, GLP-1 has many benefits which make a lot of differences compared to existing therapeutic agents. However, GLP-1 is not used clinically because it could be degraded quickly by serine proteinase such as dipeptidyl peptidase-IV (DPP-IV) distributed widely in vivo and loses activity. Therefore, researchers have focused on developing GLP-1 analogues which are long lasting and resistant to peptidase degradation, and are dipeptidyl peptidase-IV inhibitors.
X-Proline dipeptide can be removed from N-terminus of polypeptide by dipeptidyl peptidase-IV which is an exopeptidase of glycoprotein and serine in the cell membrane. DPP-IV is widely distributed all over the body tissues comprising endothelial cells of intestine and intestinal mucosal vessel. DPP-IV is expressed in T-cells of cardiovascular system, which is equated with T cell activation marker CD26. The data of a model of the cardiovascular system indicate that DPP-IV has a potential coactivated effect during T cell activation process. In addition, DPP-IV also shows degradation of polypeptide of immunomodulator, endocrine and nerve.
DPP-IV inhibitors could increase the level of GLP-1 which is undegraded and has biological activity, and provide alternative therapies for type II diabetes. In addition, DPP-IV inhibitors are effective orally compared with incretin analogues. Glucose control could be improved by inhibiting the activity of DPP-IV. The advantage of DPP-IV inhibitors is that the release of insulin may be increased. Meanwhile, the DPP-IV inhibitors would not increase the risk of hypoglycemia. However, DPP-IV is as a member of the exopeptidase family, there are needs for DPP-IV inhibitors having high selectivity in inhibiting only the activity of DPP-IV and having no effect on other DPPs.